{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T06:44:46Z","timestamp":1774939486169,"version":"3.50.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82201574"],"award-info":[{"award-number":["82201574"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"crossref","award":["2021A1515110573"],"award-info":[{"award-number":["2021A1515110573"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Special Project for Clinical and Basic Sci&Tech Innovation of Guangdong Medical University","award":["GDMULCJC2024158"],"award-info":[{"award-number":["GDMULCJC2024158"]}]},{"name":"Special Project for Clinical and Basic Sci&Tech Innovation of Guangdong Medical University","award":["GDMULCJC2024129"],"award-info":[{"award-number":["GDMULCJC2024129"]}]},{"name":"Characteristic Innovation Project of Ordinary Universities in Guangdong Province","award":["2020KTSCX046"],"award-info":[{"award-number":["2020KTSCX046"]}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Backgroud<\/jats:title>\n                    <jats:p>VPS35, a core component of the retromer complex, has been closely associated with neurodegenerative disorders, particularly Parkinson\u2019s disease (PD). The VPS35 D620N mutation has been identified as a pathogenic variant in familial PD. However, the precise mechanisms by which VPS35 and its D620N mutant influence neurogenesis remain poorly understood. This study explores the role of the VPS35 D620N mutation in PD-related neurogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      Protein-protein interaction (PPI) and KEGG pathway analyses identified key regulatory molecules, including TP53, AKT1, and SRC, with the PI3K-Akt signaling pathways emerging as central contributors to mutation-induced neurogenic deficits and ferroptosis in PD. Molecular docking analysis demonstrated strong binding affinities between VPS35 D620N and these hub targets, particularly PI3K. Furthermore, molecular dynamics simulations confirmed the stable interaction between VPS35 D620N and key hub proteins. Immunofluorescence staining revealed that the D620N mutation significantly impaired the neurogenic capacity of neural precursor cells both\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      , accompanied by increased cell death. Cellular experiments further revealed that the D620N mutation promoted cell death, increased lipid peroxidation and reactive oxygen species (ROS) levels, reduced the expression of ferroptosis-related proteins such as GPX4, and downregulated components of the PI3K-Akt signaling pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study highlights that the VPS35 D620N mutation may impair neurogenesis through ferroptosis mediated by dysregulation of the PI3K-Akt pathway, offering novel mechanistic insights into its role in PD pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2025.1692687","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T06:26:02Z","timestamp":1764051962000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["VPS35 D620N mutation impairs neurogenesis and promotes ferroptosis in Parkinson\u2019s disease by using molecular docking, molecular dynamic simulation, and cellular model"],"prefix":"10.3389","volume":"17","author":[{"given":"Mei","family":"Jiang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zijie","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zixiong","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiankai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongxia","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojun","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.neuropharm.2008.04.005","article-title":"cAMP promotes neurite outgrowth and extension through protein kinase A but independently of Erk activation in cultured rat motoneurons","volume":"55","author":"Aglah","year":"2008","journal-title":"Neuropharmacology"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"5949","DOI":"10.1523\/JNEUROSCI.3621-17.2018","article-title":"Increased microglial activity, impaired adult hippocampal neurogenesis, and depressive-like behavior in microglial VPS35-depleted mice","volume":"38","author":"Appel","year":"2018","journal-title":"J. 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